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Compounds of the formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein, R.sup.1 is
optionally substituted tetrazolyl, R.sup.2 is optionally substituted
phenyl, optionally substituted pyridinyl or optionally substituted
thienyl, and R.sup.3, R.sup.4, R.sup.5, R.sup.6 R.sup.7 and R.sup.8 are
as defined herein. Also provided are methods of using the compounds for
treating diseases associated with the P2X.sub.3 and/or a P2X.sub.2/3
receptor antagonist and methods of making the compounds.

1. A compound of formula I: ##STR00078## or a pharmaceutically acceptable
salt thereof,wherein:R.sup.1 is optionally substituted tetrazolyl;R.sup.2
is optionally substituted phenyl, optionally substituted pyridinyl,
optionally substituted pyrimidinyl, optionally substituted pyridazinyl or
optionally substituted thiophenyl;R.sup.3
is:hydrogen;C.sub.1-6alkyl;hetero-C.sub.1-6alkyl; orcyano;R.sup.4
is:hydrogen;C.sub.1-6alkyl; orhetero-C.sub.1-6alkyl;or R.sup.3 and
R.sup.4 together with the atom to which they are attached may form a
C.sub.3-6 carbocyclic ring;R.sup.5
is:C.sub.1-6alkyl;hetero-C.sub.1-6alkyl;halo-C.sub.1-6alkyl;N--C.sub.1-6a-
lkylamino;N,N-di-(C.sub.1-6alkyl)-amino;C.sub.3-7cycloalkyl;aryl;heteroary-
l;heterocyclyl;C.sub.3-7cycloalkyl-C.sub.1-6alkyl;heteroaryl-C.sub.1-6alky-
l;heterocyclyl-C.sub.1-6alkyl;aryloxy-C.sub.1-6alkyl;--(CR.sup.aR.sup.b).s-
ub.m--C(O)--R.sup.8 wherein:m is 0 or 1;R.sup.a and R.sup.b each
independently is:hydrogen; orC.sub.1-6alkyl; andR.sup.8
is:hydrogen;C.sub.1-6alkyl;hetero-C.sub.1-6alkyl;C.sub.3-7cycloalkyl;aryl-
;heteroaryl;heterocyclyl;C.sub.3-7cycloalkyl-C.sub.1-6alkyl;aryl-C.sub.1-6-
alkyl;heteroaryl-C.sub.1-6alkyl;heterocyclyl-C.sub.1-6alkyl;C.sub.3-7cyclo-
alkyloxy;aryloxy;heteroaryloxy;heterocyclyloxy;C.sub.3-7cycloalkyloxy-C.su-
b.1-6alkyl;aryloxy-C.sub.1-6alkyl;heteroaryloxy-C.sub.1-6alkyl;heterocycly-
loxy-C.sub.1-6alkyl; or--NR.sup.9R.sup.10, wherein:R.sup.9 is: hydrogen;
or C.sub.1-6alkyl; andR.sup.10 is: hydrogen; C.sub.1-6alkyl;
hetero-C.sub.1-6alkyl; C.sub.3-7cycloalkyl; aryl; heteroaryl;
heterocyclyl; C.sub.3-7cycloalkyl-C.sub.1-6alkyl; aryl-C.sub.1-6alkyl;
heteroaryl-C.sub.1-6alkyl; or heterocyclyl-C.sub.1-6alkyl; andor R.sup.4
and R.sup.5 together with the atom to which they are attached may form a
C.sub.3-6 carbocyclic ring that is optionally substituted with hydroxy;or
R.sup.4 and R.sup.5 together with the atom to which they are attached may
form a C.sub.4-6 heterocyclic ring containing one or two heteroatoms each
independently selected from O, N and S;or R.sup.3, R.sup.4 and R.sup.5
together with the atom to which they are attached may form a six-membered
heteroaryl containing one or two nitrogen atoms, and which is optionally
substituted with halo, amino or C.sub.1-6alkyl;R.sup.6
is:hydrogen;C.sub.1-6alkyl;C.sub.1-6alkyloxy;halo;C.sub.1-6haloalkyl;
orcyano; andR.sup.7 and R.sup.8 each independently
is:C.sub.1-6alkyl;C.sub.1-6alkyloxy;halo;C.sub.1-6haloalkyl; orcyano;or
one of R.sup.7 and R.sup.8
is:C.sub.1-6alkyl;C.sub.1-6alkyloxy;halo;C.sub.1-6haloalkyl; orcyano;and
the other is hydrogen.

7. The compound of claim 1, wherein one of R.sup.7 and R.sup.8 is halo or
C.sub.1-4alkoxy and the other is hydrogen.

8. The compound of claim 1, wherein one of R.sup.7 and R.sup.8 is fluoro
and the other is hydrogen.

9. The compound of claim 1, wherein R.sup.1 is tetrazol-1-yl optionally
substituted at the 5-position with C.sub.1-6alkyl, halo-C.sub.1-6alkyl,
hetero-C.sub.1-6alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6cycloalkyl-C.sub.1-6alkyl or cyano.

10. The compound of claim 1, wherein R.sup.2 is phenyl optionally
substituted once, twice or three times with a group or groups each
independently selected from C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano.

11. The compound of claim 1, wherein R.sup.2 is pyridin-2-yl optionally
substituted once or twice with a group or groups each independently
selected from C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano.

12. The compound of claim 1, wherein R.sup.4 and R.sup.5 together with the
atom to which they are attached form a C.sub.3-6 carbocyclic ring that is
optionally substituted with hydroxy.

13. The compound of claim 1, wherein R.sup.4 and R.sup.5 together with the
atom to which they are attached form a cyclopropyl group.

14. The compound of claim 1, wherein R.sup.1 is tetrazol-1-yl optionally
substituted at the 5-position with isopropyl or trifluoromethyl.

15. The compound of claim 1, wherein R.sup.5 is heteroaryl selected from
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or thiazolyl,
each of which may be optionally substituted once or twice with a group or
groups independently selected from methyl, ethyl, n-propyl, fluoro,
chloro, amino, methylamino and dimethylamino.

20. A method for treating a respiratory disorder selected from chronic
obstructive pulmonary disorder (COPD), asthma, and bronchospasm, said
method comprising administering to a subject in need thereof an effective
amount of a compound of claim 1.

[0002]This invention pertains to compounds useful for treatment of
diseases associated with P2X purinergic receptors, and more particularly
to P2X.sub.3 and/or P2X.sub.2/3 antagonists usable for treatment of
genitourinary, pain, gastrointestinal and respiratory diseases,
conditions and disorders.

BACKGROUND OF THE INVENTION

[0003]The urinary bladder is responsible for two important physiological
functions: urine storage and urine emptying. This process involves two
main steps: (1) the bladder fills progressively until the tension in its
walls rises above a threshold level; and (2) a nervous reflex, called the
micturition reflex, occurs that empties the bladder or, if this fails, at
least causes a conscious desire to urinate. Although the micturition
reflex is an autonomic spinal cord reflex, it can also be inhibited or
mediated by centers in the cerebral cortex or brain.

[0004]Purines, acting via extracellular purinoreceptors, have been
implicated as having a variety of physiological and pathological roles.
(See, Burnstock (1993) Drug Dev. Res. 28:195-206.) ATP, and to a lesser
extent, adenosine, can stimulate sensory nerve endings resulting in
intense pain and a pronounced increase in sensory nerve discharge. ATP
receptors have been classified into two major families, the P2Y- and
P2X-purinoreceptors, on the basis of molecular structure, transduction
mechanisms, and pharmacological characterization. The P2Y-purinoreceptors
are G-protein coupled receptors, while the P2X-purinoreceptors are a
family of ATP-gated cation channels. Purinergic receptors, in particular,
P2X receptors, are known to form homomultimers or heteromultimers. To
date, cDNAs for several P2X receptors subtypes have been cloned,
including: six homomeric receptors, P2X.sub.1; P2X.sub.2; P2X.sub.3;
P2.times.4; P2X.sub.5; and P2X.sub.7; and three heteromeric receptors
P2X.sub.2/3, P2X.sub.4/6, P2X.sub.1/5 (See, e.g., Chen, et al. (1995)
Nature 377:428-431; Lewis, et al. (1995) Nature 377:432-435; and
Burnstock (1997) Neurophamacol. 36:1127-1139). The structure and
chromosomal mapping of mouse genomic P2X.sub.3 receptor subunit has also
been described (Souslova, et al. (1997) Gene 195:101-111). In vitro,
co-expression of P2X.sub.2 and P2X.sub.3 receptor subunits is necessary
to produce ATP-gated currents with the properties seen in some sensory
neurons (Lewis, et al. (1995) Nature 377:432-435).

[0005]P2X receptor subunits are found on afferents in rodent and human
bladder urothelium. Data exists suggesting that ATP may be released from
epithelial/endothelial cells of the urinary bladder or other hollow
organs as a result of distention (Burnstock (1999) J. Anatomy
194:335-342; and Ferguson et al. (1997) J. Physiol. 505:503-511). ATP
released in this manner may serve a role in conveying information to
sensory neurons located in subepithelial components, e.g., suburothelial
lamina propria (Namasivayam, et al. (1999) BJU Intl. 84:854-860). The P2X
receptors have been studied in a number of neurons, including sensory,
sympathetic, parasympathetic, mesenteric, and central neurons (Zhong, et
al. (1998) Br. J. Pharmacol. 125:771-781). These studies indicate that
purinergic receptors play a role in afferent neurotransmission from the
bladder, and that modulators of P2X receptors are potentially useful in
the treatment of bladder disorders and other genitourinary diseases or
conditions.

[0006]Recent evidence also suggests a role of endogenous ATP and
purinergic receptors in nociceptive responses in mice (Tsuda, et al.
(1999) Br. J. Pharmacol. 128:1497-1504). ATP-induced activation of P2X
receptors on dorsal root ganglion nerve terminals in the spinal cord has
been shown to stimulate release of glutamate, a key neurotransmitter
involved in nociceptive signaling (Gu and MacDermott, Nature 389:749-753
(1997)). P2X.sub.3 receptors have been identified on nociceptive neurons
in the tooth pulp (Cook et al., Nature 387:505-508 (1997)). ATP released
from damaged cells may thus lead to pain by activating P2X.sub.3 and/or
P2X.sub.2/3 containing receptors on nociceptive sensory nerve endings.
This is consistent with the induction of pain by intradermally applied
ATP in the human blister-base model (Bleehen, Br J Pharmacol 62:573-577
(1978)). P2X antagonists have been shown to be analgesic in animal models
(Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol 350:618-625
(1994)). This evidence suggests that P2X.sub.2 and P2X.sub.3 are involved
in nociception, and that modulators of P2X receptors are potentially
useful as analgesics.

[0009]There is accordingly a need for compounds that act as modulators of
P2X receptors, including antagonists of P2X.sub.3 and P2X.sub.2/3
receptors, as well as a need for methods of treating diseases, conditions
and disorders mediated by P2X.sub.3 and/or P2X.sub.2/3 receptors. The
present invention satisfies these needs as well as others.

[0067]or R.sup.4 and R.sup.5 together with the atom to which they are
attached may form a C.sub.3-6 carbocyclic ring that is optionally
substituted with hydroxy;

[0068]or R.sup.4 and R.sup.5 together with the atom to which they are
attached may form a C.sub.4-6 heterocyclic ring containing one or two
heteroatoms each independently selected from O, N and S;

[0069]or R.sup.3, R.sup.4 and R.sup.5 together with the atom to which they
are attached may form a six-membered heteroaryl containing one or two
nitrogen atoms, and which is optionally substituted with halo, amino or
C.sub.1-6alkyl;

[0083]or one of R.sup.7 and R.sup.8 is: [0084]C.sub.1-6alkyl;
[0085]C.sub.1-6alkyloxy; [0086]halo; [0087]C.sub.1-6haloalkyl; or
[0088]cyano;

[0089]and the other is hydrogen.

[0090]The invention also provides and pharmaceutical compositions
comprising the compounds, methods of using the compounds, and methods of
preparing the compounds.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0091]Unless otherwise stated, the following terms used in this
Application, including the specification and claims, have the definitions
given below. It must be noted that, as used in the specification and the
appended claims, the singular forms "a", "an," and "the" include plural
referents unless the context clearly dictates otherwise.

[0092]"Agonist" refers to a compound that enhances the activity of another
compound or receptor site.

[0093]"Alkyl" means the monovalent linear or branched saturated
hydrocarbon moiety, consisting solely of carbon and hydrogen atoms,
having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl
group of one to six carbon atoms, i.e. C.sub.1-C.sub.6alkyl. Examples of
alkyl groups include, but are not limited to, methyl, ethyl, propyl,
isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl,
dodecyl, and the like.

[0094]"Alkenyl" means a linear monovalent hydrocarbon radical of two to
six carbon atoms or a branched monovalent hydrocarbon radical of three to
six carbon atoms, containing at least one double bond, e.g., ethenyl,
propenyl, and the like.

[0095]"Alkynyl" means a linear monovalent hydrocarbon radical of two to
six carbon atoms or a branched monovalent hydrocarbon radical of three to
six carbon atoms, containing at least one triple bond, e.g., ethynyl,
propynyl, and the like.

[0096]"Alkylene" means a linear saturated divalent hydrocarbon radical of
one to six carbon atoms or a branched saturated divalent hydrocarbon
radical of three to six carbon atoms, e.g., methylene, ethylene,
2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,
and the like.

[0097]"Alkoxy" and "alkyloxy", which may be used interchangeably, mean a
moiety of the formula --OR, wherein R is an alkyl moiety as defined
herein. Examples of alkoxy moieties include, but are not limited to,
methoxy, ethoxy, isopropoxy, and the like.

[0098]"Alkoxyalkyl" means a moiety of the formula R.sup.a--O--R.sup.b--,
where R.sup.a is alkyl and R.sup.b is alkylene as defined herein.
Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl,
3-methoxypropyl, 1-methyl-2-methoxyethyl,
1-(2-methoxyethyl)-3-methoxypropyl, and
1-(2-methoxyethyl)-3-methoxypropyl.

[0099]"Alkylcarbonyl" means a moiety of the formula --R'--R'', where R' is
oxo and R'' is alkyl as defined herein.

[0100]"Alkylsulfonyl" means a moiety of the formula --R'--R'', where R' is
--SO.sub.2-- and R'' is alkyl as defined herein.

[0101]"Alkylsulfonylalkyl means a moiety of the formula --R'--R''--R'''
where where R' is alkylene, R'' is --SO.sub.2-- and R''' is alkyl as
defined herein.

[0102]"Alkylamino means a moiety of the formula --NR--R' wherein R is
hydrogen or alkyl and R' is alkyl as defined herein.

[0103]"Alkoxyamino" means a moiety of the formula --NR--OR' wherein R is
hydrogen or alkyl and R' is alkyl as defined herein.

[0104]"Alkylsulfanyl" means a moiety of the formula --SR wherein R is
alkyl as defined herein.

[0105]"Aminoalkyl" means a group --R--R' wherein R' is amino and R is
alkylene as defined herein. "Aminoalkyl" includes aminomethyl,
aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety
of "aminoalkyl" may be substituted once or twice with alkyl to provide
"alkylaminoalkyl" and "dialkylaminoalkyl" respectively.

[0106]"Alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl,
methylaminopropyl, ethylaminoethyl and the like. "Dialkylaminoalkyl"
includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,
N-methyl-N-ethylaminoethyl, and the like.

[0107]"Aminoalkoxy" means a group --OR--R' wherein R' is amino and R is
alkylene as defined herein.

[0108]"Alkylsulfonylamido" means a moiety of the formula --NR'SO.sub.2--R
wherein R is alkyl and R' is hydrogen or alkyl.

[0109]"Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of the
formula --R--O--C(O)--NR'R'' wherein R is alkylene and R', R'' each
independently is hydrogen or alkyl as defined herein.

[0110]"Alkynylalkoxy" means a group of the formula --O--R--R' wherein R is
alkylene and R' is alkynyl as defined herein.

[0111]"Antagonist" refers to a compound that diminishes or prevents the
action of another compound or receptor site.

[0113]"Arylalkyl" and "Aralkyl", which may be used interchangeably, mean a
radical-R.sup.aR.sup.b where R.sup.a is an alkylene group and R.sup.b is
an aryl group as defined herein; e.g., phenylalkyls such as benzyl,
phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples
of arylalkyl.

[0114]"Arylsulfonyl means a group of the formula --SO.sub.2--R wherein R
is aryl as defined herein.

[0115]"Aryloxy" means a group of the formula --O--R wherein R is aryl as
defined herein.

[0116]"Aralkyloxy" means a group of the formula --O--R--R'' wherein R is
alkylene and R' is aryl as defined herein.

[0117]"Cyanoalkyl" means a moiety of the formula --R'R'', where R' is
alkylene as defined herein and R'' is cyano or nitrile.

[0119]"Cycloalkylalkyl" means a moiety of the formula --R'R'', where R' is
alkylene and R'' is cycloalkyl as defined herein.

[0120]"Heteroalkyl" means an alkyl radical as defined herein wherein one,
two or three hydrogen atoms have been replaced with a substituent
independently selected from the group consisting of --OR.sup.a,
--NR.sup.bR.sup.c, and --S(O).sub.nR.sup.d (where n is an integer from 0
to 2), with the understanding that the point of attachment of the
heteroalkyl radical is through a carbon atom, wherein R.sup.a is
hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R.sup.b and
R.sup.c are independently of each other hydrogen, acyl, alkyl,
cycloalkyl, or cycloalkylalkyl; and when n is 0, R.sup.d is hydrogen,
alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R.sup.d is
alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or
dialkylamino. Representative examples include, but are not limited to,
2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,
2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl,
2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl,
3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl,
aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl,
methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

[0122]Heteroarylalkyl" or "heteroaralkyl" means a group of the formula
--R--R' wherein R is alkylene and R' is heteroaryl as defined herein.

[0123]"Heteroarylsulfonyl means a group of the formula --SO.sub.2--R
wherein R is heteroaryl as defined herein.

[0124]"Heteroaryloxy" means a group of the formula --O--R wherein R is
heteroaryl as defined herein.

[0125]"Heteroaralkyloxy" means a group of the formula --O--R--R'' wherein
R is alkylene and R' is heteroaryl as defined herein.

[0126]The terms "halo", "halogen" and "halide", which may be used
interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

[0127]"Haloalkyl" means alkyl as defined herein in which one or more
hydrogen has been replaced with same or different halogen. Exemplary
haloalkyls include --CH.sub.2Cl, --CH.sub.2CF.sub.3, --CH.sub.2CCl.sub.3,
perfluoroalkyl (e.g., --CF.sub.3), and the like.

[0128]"Haloalkoxy" means a moiety of the formula --OR, wherein R is a
haloalkyl moiety as defined herein. An exemplary haloalkoxy is
difluoromethoxy.

[0129]"Heterocycloamino" means a saturated ring wherein at least one ring
atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene
group.

[0131]"Heterocyclylalkyl" means a moiety of the formula --R--R' wherein R
is alkylene and R' is heterocyclyl as defined herein.

[0132]"Heterocyclyloxy" means a moiety of the formula --OR wherein R is
heterocyclyl as defined herein.

[0133]"Heterocyclylalkoxy" means a moiety of the formula --OR--R' wherein
R is alkylene and R' is heterocyclyl as defined herein.

[0134]"Hydroxyalkoxy" means a moiety of the formula --OR wherein R is
hydroxyalkyl as defined herein.

[0135]"Hydroxyalkylamino" means a moiety of the formula --NR--R' wherein R
is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.

[0136]"Hydroxyalkylaminoalkyl" means a moiety of the formula --R--NR'--R''
wherein R is alkylene, R' is hydrogen or alkyl, and R'' is hydroxyalkyl
as defined herein.

[0137]"Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the
formula --R--(CO)--OH where R is alkylene as defined herein.

[0138]"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means
a group of the formula --R--C(O)--O--R--OH wherein each R is alkylene and
may be the same or different.

[0139]"Hydroxyalkyl" means an alkyl moiety as defined herein, substituted
with one or more, preferably one, two or three hydroxy groups, provided
that the same carbon atom does not carry more than one hydroxy group.
Representative examples include, but are not limited to, hydroxymethyl,
2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,
2,3-dihydroxybutyl, 3,4-dihydroxybutyl and
2-(hydroxymethyl)-3-hydroxypropyl

[0140]"Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein
wherein one, two or three hydrogen atoms in the cycloalkyl radical have
been replaced with a hydroxy substituent. Representative examples
include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the
like.

[0141]"Urea" or "ureido" means a group of the formula
--NR'--C(O)--NR''R''' wherein R', R'' and R''' each independently is
hydrogen or alkyl.

[0142]"Carbamate" means a group of the formula --O--C(O)--NR'R'' wherein
R' and R'' each independently is hydrogen or alkyl.

[0143]"Carboxy" means a group of the formula --O--C(O)--OH.

[0144]"Sulfonamido" means a group of the formula --SO.sub.2--NR'R''
wherein R', R'' and R''' each independently is hydrogen or alkyl.

[0145]"Optionally substituted", when used in association with "aryl",
phenyl", "heteroaryl" "cycloalkyl" or "heterocyclyl", means an aryl,
phenyl, heteroaryl, cyclohexyl or heterocyclyl which is optionally
substituted independently with one to four substituents, preferably one
or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl,
heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,
acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,
heteroalkyl, --COR (where R is hydrogen, alkyl, phenyl or phenylalkyl),
--(CR'R'').sub.n--COOR (where n is an integer from 0 to 5, R' and R'' are
independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, phenyl or phenylalkyl), or
--CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an integer from 0 to 5, R'
and R'' are independently hydrogen or alkyl, and R.sup.a and R.sup.b are,
independently of each other, hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optional
substituents for "aryl", phenyl", "heteroaryl" "cycloalkyl" or
"heterocyclyl" include alkyl, halo, haloalkyl, alkoxy, cyano, amino and
alkylsulfonyl. More preferred substituents are methyl, fluoro, chloro,
trifluoromethyl, methoxy, amino and methanesulfonyl.

[0146]"Leaving group" means the group with the meaning conventionally
associated with it in synthetic organic chemistry, i.e., an atom or group
displaceable under substitution reaction conditions. Examples of leaving
groups include, but are not limited to, halogen, alkane- or
arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,
thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,
dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,
acyloxy, and the like.

[0147]"Modulator" means a molecule that interacts with a target. The
interactions include, but are not limited to, agonist, antagonist, and
the like, as defined herein.

[0148]"Optional" or "optionally" means that the subsequently described
event or circumstance may but need not occur, and that the description
includes instances where the event or circumstance occurs and instances
in which it does not.

[0150]"Inert organic solvent" or "inert solvent" means the solvent is
inert under the conditions of the reaction being described in conjunction
therewith, including for example, benzene, toluene, acetonitrile,
tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or
dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone,
methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,
tert-butanol, dioxane, pyridine, and the like. Unless specified to the
contrary, the solvents used in the reactions of the present invention are
inert solvents.

[0151]"Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe, non-toxic,
and neither biologically nor otherwise undesirable and includes that
which is acceptable for veterinary as well as human pharmaceutical use.

[0152]"Pharmaceutically acceptable salts" of a compound means salts that
are pharmaceutically acceptable, as defined herein, and that possess the
desired pharmacological activity of the parent compound. Such salts
include:

[0154]salts formed when an acidic proton present in the parent compound
either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline
earth ion, or an aluminum ion; or coordinates with an organic or
inorganic base. Acceptable organic bases include diethanolamine,
ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the
like. Acceptable inorganic bases include aluminum hydroxide, calcium
hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[0156]It should be understood that all references to pharmaceutically
acceptable salts include solvent addition forms (solvates) or crystal
forms (polymorphs) as defined herein, of the same acid addition salt.

[0157]"Protective group" or "protecting group" means the group which
selectively blocks one reactive site in a multifunctional compound such
that a chemical reaction can be carried out selectively at another
unprotected reactive site in the meaning conventionally associated with
it in synthetic chemistry. Certain processes of this invention rely upon
the protective groups to block reactive nitrogen and/or oxygen atoms
present in the reactants. For example, the terms "amino-protecting group"
and "nitrogen protecting group" are used interchangeably herein and refer
to those organic groups intended to protect the nitrogen atom against
undesirable reactions during synthetic procedures. Exemplary nitrogen
protecting groups include, but are not limited to, trifluoroacetyl,
acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ),
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl
(BOC), and the like. The artisan in the art will know how to chose a
group for the ease of removal and for the ability to withstand the
following reactions.

[0158]"Solvates" means solvent additions forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some compounds
have a tendency to trap a fixed molar ratio of solvent molecules in the
crystalline solid state, thus forming a solvate. If the solvent is water
the solvate formed is a hydrate, when the solvent is alcohol, the solvate
formed is an alcoholate. Hydrates are formed by the combination of one or
more molecules of water with one of the substances in which the water
retains its molecular state as H.sub.2O, such combination being able to
form one or more hydrate.

[0159]"Subject" means mammals and non-mammals. Mammals means any member of
the mammalia class including, but not limited to, humans; non-human
primates such as chimpanzees and other apes and monkey species; farm
animals such as cattle, horses, sheep, goats, and swine; domestic animals
such as rabbits, dogs, and cats; laboratory animals including rodents,
such as rats, mice, and guinea pigs; and the like. Examples of
non-mammals include, but are not limited to, birds, and the like. The
term "subject" does not denote a particular age or sex.

[0161]"Disease states associated with the urinary tract" or "urinary tract
disease states" or "uropathy" used interchangeably with "symptoms of the
urinary tract" mean the pathologic changes in the urinary tract, or
dysfunction of urinary bladder smooth muscle or its innervation causing
disordered urinary storage or voiding. Symptoms of the urinary tract
include, but are not limited to, overactive bladder (also known as
detrusor hyperactivity), outlet obstruction, outlet insufficiency, and
pelvic hypersensitivity.

[0169]"Therapeutically effective amount" means an amount of a compound
that, when administered to a subject for treating a disease state, is
sufficient to effect such treatment for the disease state. The
"therapeutically effective amount" will vary depending on the compound,
disease state being treated, the severity or the disease treated, the age
and relative health of the subject, the route and form of administration,
the judgment of the attending medical or veterinary practitioner, and
other factors.

[0170]The terms "those defined above" and "those defined herein" when
referring to a variable incorporates by reference the broad definition of
the variable as well as preferred, more preferred and most preferred
definitions, if any.

[0171]"Treating" or "treatment" of a disease state includes: [0172](i)
preventing the disease state, i.e. causing the clinical symptoms of the
disease state not to develop in a subject that may be exposed to or
predisposed to the disease state, but does not yet experience or display
symptoms of the disease state. [0173](ii) inhibiting the disease state,
i.e., arresting the development of the disease state or its clinical
symptoms, or [0174](iii) relieving the disease state, i.e., causing
temporary or permanent regression of the disease state or its clinical
symptoms.

[0175]The terms "treating", "contacting" and "reacting" when referring to
a chemical reaction means adding or mixing two or more reagents under
appropriate conditions to produce the indicated and/or the desired
product. It should be appreciated that the reaction which produces the
indicated and/or the desired product may not necessarily result directly
from the combination of two reagents which were initially added, i.e.,
there may be one or more intermediates which are produced in the mixture
which ultimately leads to the formation of the indicated and/or the
desired product.

Nomenclature and Structures

[0176]In general, the nomenclature used in this Application is based on
AUTONOM.TM. v.4.0, a Beilstein Institute computerized system for the
generation of IUPAC systematic nomenclature. Chemical structures shown
herein were prepared using ISIS.RTM. version 2.2. Any open valency
appearing on a carbon, oxygen or nitrogen atom in the structures herein
indicates the presence of a hydrogen atom. Where a chiral center exists
in a structure but no specific stereochemistry is shown for the chiral
center, both enantiomers associated with the chiral structure are
encompassed by the structure.

[0177]All patents and publications identified herein are incorporated
herein by reference in their entirety.

[0235]or R.sup.4 and R.sup.5 together with the atom to which they are
attached may form a C.sub.3-6 carbocyclic ring that is optionally
substituted with hydroxy;

[0236]or R.sup.4 and R.sup.5 together with the atom to which they are
attached may form a C.sub.4-6 heterocyclic ring containing one or two
heteroatoms each independently selected from O, N and S;

[0237]or R.sup.3, R.sup.4 and R.sup.5 together with the atom to which they
are attached may form a six-membered heteroaryl containing one or two
nitrogen atoms, and which is optionally substituted with halo, amino or
C.sub.1-6alkyl;

[0251]or one of R.sup.7 and R.sup.8 is: [0252]C.sub.1-6alkyl;
[0253]C.sub.1-6alkyloxy; [0254]halo; [0255]C.sub.1-6haloalkyl; or
[0256]cyano;

[0257]and the other is hydrogen.

[0258]In many embodiments of formula I, R.sup.2 is optionally substituted
phenyl, such as phenyl optionally substituted once, twice or three times,
preferably once or twice, with any of C.sub.1-6alkyl, C.sub.1-6alkyloxy,
halo, C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl
or cyano.

[0259]In certain embodiments R.sup.2 is phenyl substituted once or twice
with halo or methyl.

[0260]In many embodiments of formula I, R.sup.2 is phenyl substituted at
the 4-position with methyl or halo and optionally substituted at the 2-
and 6-positions with halo.

[0261]In many embodiments of formula I, R.sup.2 is phenyl substituted at
the 4-position with methyl or halo and optionally substituted at the
2-position with halo.

[0271]In many embodiments of formula I, R.sup.2 is optionally substituted
pyridinyl. Exemplary pyridinyl include pyridin-2-yl, and
pyridin-2-one-1-yl, each optionally substituted once, twice or three
times, preferably once or twice, with any of C.sub.1-6alkyl,
C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl,
C.sub.1-6alkylsulfonyl or cyano. Preferred pyridyl include
4-methyl-pyridin-2-yl, 4-fluoro-pyridin-2-yl and
4-methyl-pyridin-2-one-1-yl.

[0272]In certain embodiments of formula I, R.sup.2 is pyridin 2-yl
substituted with methyl or halo at the 5-position.

[0273]In certain embodiments of formula I, R.sup.2 is pyridin 2-yl
substituted with methyl or halo at the 5-position and optionally
substituted with halo at the 3-position.

[0282]In certain embodiments of formula I, R.sup.2 is optionally
substituted pyridazinyl. In such embodiments R.sup.2 may be
6-chloro-pyridazinyl or 6-methyl-pyridazinyl, preferably
6-chloro-pyridazinyl.

[0283]In certain embodiments of formula I, R.sup.2 is optionally
substituted thiophenyl. In such embodiments R.sup.2 may be thiophen-2-yl
optionally substituted with C.sub.1-6alkyl or halo. Preferred thiophenyl
include 3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl and
5-chloro-thiophen-2-yl.

[0284]In many embodiments of formula I, R.sup.6 is hydrogen. In certain
embodiments of formula I, R.sup.6 may be methyl.

[0285]In many embodiments of formula I, R.sup.3 is hydrogen.

[0286]In many embodiments of formula I, R.sup.3 is C.sub.1-6alkyl. A
preferred C.sub.1-6alkyl in such embodiments is methyl.

[0287]In many embodiments of formula I, R.sup.4 is C.sub.1-6alkyl. A
preferred C.sub.1-6alkyl in such embodiments is methyl.

[0288]In many embodiments of formula I, R.sup.3 is hydrogen and R.sup.4 is
C.sub.1-6alkyl, preferably methyl.

[0290]In certain embodiments of formula I, R.sup.3 and R.sup.4 together
with the atom to which they are attached may form a C.sub.3-6 carbocyclic
ring.

[0291]In certain embodiments of formula I, R.sup.3 and R.sup.4 together
with the atom to which they are attached may form a cyclopropyl group.

[0292]In certain embodiments of formula I, R.sup.4 and R.sup.5 together
with the atom to which they are attached form a C.sub.3-6 carbocyclic
ring that is optionally substituted with hydroxy.

[0293]In certain embodiments of formula I, R.sup.4 and R.sup.5 together
with the atom to which they are attached form a cyclopropyl.

[0294]In certain embodiments of formula I, R.sup.3 is hydrogen and R.sup.4
and R.sup.5 together with the atom to which they are attached form a
cyclopropyl.

[0295]In certain embodiments of formula I, R.sup.3 is hydrogen and R.sup.4
and R.sup.5 together with the atom to which they are attached form a
cyclopentyl optionally substituted with hydroxy.

[0296]In certain embodiments of formula I, R.sup.4 and R.sup.5 together
with the atom to which they are attached form a C.sub.4-6 heterocyclic
ring containing one or two heteroatoms each independently selected from
O, N and S.

[0297]In certain embodiments of formula I, R.sup.4 and R.sup.5 together
with the atom to which they are attached form a piperidinyl group or
oxetanyl ring group.

[0298]In certain embodiments of formula I, R.sup.4 and R.sup.5 together
with the atom to which they are attached form a piperidin-3-yl group or
an oxetan-3-yl group.

[0299]In certain embodiments of formula I, R.sup.3, R.sup.4 and R.sup.5
together with the atom to which they are attached form a six-membered
heteroaryl containing one or two nitrogen atoms, and which is optionally
substituted with halo, amino or C.sub.1-6alkyl.

[0300]In certain embodiments of formula I, R.sup.3, R.sup.4 and R.sup.5
together with the atom to which they are attached form a heteroaryl
selected from 2-oxo-1,2-dihydro-pyrimidinyl, pyridinyl, pyrimidinyl,
pyridazinyl or pyridazinyl, each optionally substituted with methyl or
amino.

[0301]In certain embodiments of formula I, R.sup.3, R.sup.4 and R.sup.5
together with the atom to which they are attached form a heteroaryl
selected from 2-oxo-1,2-dihydro-pyrimidin-4-yl,
2-oxo-1,2-dihydro-pyrimidin-4-yl,
1-methyl-2-oxo-1,2-dihydro-pyrimidin-4-yl, 6-methyl-pyridin-3-yl,
pyridazin-4-yl, 6-amino-pyridin-2-yl, 2-aminopyrimidin-4-yl or
2-amino-pyrimidin-3-yl.

[0302]In many embodiments of formula I, R.sup.1 is tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl.

[0303]In certain embodiments of formula I, R.sup.1 is tetrazol-5-yl
optionally substituted at the 1-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, hetero-C.sub.1-6alkyl, C.sub.3-6-cycloalkyl,
C.sub.3-6cycloalkyl-C.sub.1-6alkyl or cyano. Preferably in such
embodiments the 1-position is substituted with C.sub.1-6alkyl.

[0319]In certain embodiments where R.sup.5 is heteroaryl, such heteroaryl
may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl,
imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl,
oxadiazolyl, 3-oxo-2,3-dihydro-isoxazolyl, tetrazolyl,
imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl,
imidazo[4,5-b]pyridinyl, and benzimidazolyl, each of which may be
optionally substituted one, two or three times with a group or groups
independently selected from C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxy-C.sub.1-6alkyl, halo-C.sub.1-6alkyl, halo, amino,
N--C.sub.1-6alkyl-amino, or N,N-di-(C.sub.1-6alkyl)-amino. More
preferably, such heteroaryl may be optionally substituted once or twice
with a group or groups independently selected from methyl, ethyl,
n-propyl, fluoro, chloro, trifluoromethyl, amino, methylamino or
dimethylamino.

[0320]In certain embodiments where R.sup.5 is heteroaryl, such heteroaryl
may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or
thiazolyl, each of which may be optionally substituted once or twice with
a group or groups independently selected from methyl, ethyl, n-propyl,
fluoro, chloro, amino, methylamino or dimethylamino.

[0321]In certain embodiments where R.sup.5 is heteroaryl, such heteroaryl
may be pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be
optionally substituted once or twice with a group or groups independently
selected from methyl, fluoro, chloro, amino, methylamino or
dimethylamino.

[0324]In embodiments where R.sup.5 is heterocyclyl-C.sub.1-6alkyl, such
heterocyclyl-C.sub.1-6alkyl may be heterocyclyl-methyl such as
morpholinomethyl, piperidinyl-methyl, piperazinyl-methyl,
thiomorpholinylmethyl, pyrrolidinylmethyl, or azetidinylmethyl, the
heterocyclyl portion of each of which may be optionally substituted once
or twice with a group or groups independently selected from methyl,
methoxy, halo, methanesulfonyl, oxo or acetyl.

[0358]R.sup.5 is: hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl;
piperidin-1-yl methyl optionally substituted at the 4-position with
methyl, methanesulfonyl or acetyl; 1,1,-dioxo-thiomorpholin-1-yl;
piperidin-1-yl-methyl optionally substituted once or twice with a group
or groups selected independently from methyl, methoxy or halo; pyridinyl;
pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; wherein the
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl
each may be optionally substituted once or twice with a group or groups
selected independently from methyl, methylamino, dimethylamino and halo.

[0364]R.sup.5 is: hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl;
piperidin-1-yl methyl optionally substituted at the 4-position with
methyl, methanesulfonyl or acetyl; 1,1,-dioxo-thiomorpholin-1-yl;
piperidin-1-yl optionally substituted once or twice with a group or
groups selected independently from methyl, methoxy or halo; pyridinyl;
pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; wherein the
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl
each may be optionally substituted once or twice with a group or groups
selected independently from methyl, methylamino, dimethylamino and halo.

[0365]In certain embodiments of formula I:

[0366]R.sup.1 is tetrazol-1-yl optionally substituted at the 5-position
with C.sub.1-6alkyl, halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl, C.sub.3-6-cycloalkyl, or
C.sub.3-6cycloalkyl-C.sub.1-6alkyl;

[0397]In certain embodiments of the invention where R.sup.2 is optionally
substituted phenyl, R.sup.3 is hydrogen and R.sup.4 is methyl, the
subject compounds may be represented by formula IIa or formula IIb:

[0404]In certain embodiments of the invention where R.sup.2 is optionally
substituted pyridinyl, R.sup.3 is hydrogen and R.sup.4 is methyl, the
subject compounds may be represented by formula IVa or formula IVb:

[0409]hetero-C.sub.1-6alkyl selected from
C.sub.1-6alkyloxy-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl,
C.sub.1-6alkylsulfanyl-C.sub.1-6alkyl,
C.sub.1-6alkyl-sulfinyl-C.sub.1-6alkyl,
C.sub.1-6alkyl-sulfonyl-C.sub.1-6alkyl, amino-C.sub.1-6alkyl,
N--C.sub.1-6alkylamino-C.sub.1-6alkyl, and
N,N-di-C.sub.1-6alkylamino-C.sub.1-6alkyl, the alkyl portions of which
may be optionally substituted with halo;

[0414]C.sub.3-7cycloalkyl-C.sub.1-6alkyl selected from
cyclopropyl-C.sub.1-6alkyl, cyclobutyl-C.sub.1-6alkyl,
cyclopentyl-C.sub.1-6alkyl and cyclohexyl-C.sub.1-6alkyl, the cycloalkyl
portion of each being optionally substituted;

[0421]hetero-C.sub.1-6alkyl selected from
C.sub.1-6alkyloxy-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl,
C.sub.1-6alkylsulfanyl-C.sub.1-6alkyl,
C.sub.1-6alkyl-sulfinyl-C.sub.1-6alkyl,
C.sub.1-6alkyl-sulfonyl-C.sub.1-6alkyl, amino-C.sub.1-6alkyl,
N--C.sub.1-6alkylamino-C.sub.1-6alkyl, and
N,N-di-C.sub.1-6alkylamino-C.sub.1-6alkyl, the alkyl portions of which
may be optionally substituted with halo;

[0426]C.sub.3-7cycloalkyl-C.sub.1-6alkyl selected from
cyclopropyl-C.sub.1-6alkyl, cyclobutyl-C.sub.1-6alkyl,
cyclopentyl-C.sub.1-6alkyl and cyclohexyl-C.sub.1-6alkyl, the cycloalkyl
portion of each being optionally substituted;

[0440]In certain embodiments of any of formulas I, IIa, IIb, IIc, IIIa,
IIIb, IIIc, IVa, IVb or IVc, R.sup.5 is aryloxy-C.sub.1-6alkyl selected
from phenoxy-C.sub.1-6alkyl and naphthyloxy-C.sub.1-6alkyl, the aryl
portion of each being optionally substituted.

[0486]In certain embodiments of formula I, R.sup.1 is: tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and

[0509]In certain embodiments of formula I: R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is C.sub.1-6alkyl. In such embodiments R.sup.5 may be
C.sub.1-6alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-pentyl and isopentyl.

[0510]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is C.sub.1-6alkyloxy-C.sub.1-6alkyl. In such
embodiments R.sup.5 may be C.sub.1-6alkyloxy-C.sub.1-6alkyl selected from
methoxymethyl, ethoxymethyl, 2-(methoxy)-ethyl, 2-(ethoxy)-ethyl,
3-(methoxy)-propyl, 3-(ethoxy)-propyl, 3-methoxy-3-methyl-butyl,
4-methoxy-butyl, and 4-methoxy-4-methyl-pentyl.

[0511]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is C.sub.1-6alkylsulfanyl-C.sub.1-6alkyl. In such
embodiments R.sup.5 may be C.sub.1-6alkylsulfanyl-C.sub.1-6alkyl selected
from methylsulfanylmethyl, ethylsulfanylmethyl, 2-(methylsulfanyl)-ethyl,
2-(ethylsulfanyl)-ethyl, 3-(methylsulfanyl)-propyl, 3-(ethanyl)-propyl,
3-methanesulfanyl-3-methyl-butyl, 4-methanesulfanyl-butyl, and
4-methylsulfanyl-4-methyl-pentyl.

[0512]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is C.sub.1-6alkylsulfonyl-C.sub.1-6alkyl. In such
embodiments R.sup.5 may be C.sub.1-6alkylsulfonyl-C.sub.1-6alkyl selected
from methylsulfonylmethyl, ethylsulfanylmethyl, 2-(methylsulfonyl)-ethyl,
2-(ethylsulfonyl)-ethyl, 3-(methylsulfonyl)-propyl, 3-(ethanyl)-propyl,
3-methanesulfonyl-3-methyl-butyl, 4-methanesulfonyl-butyl, and
4-methylsulfonyl-4-methyl-pentyl.

[0513]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is hydroxy-C.sub.1-6alkyl. In such embodiments
R.sup.5 may be hydroxy-C.sub.1-6alkyl selected from hydroxymethyl,
2-hydroxy-ethyl, 3-hydroxy-propyl, 2-hydroxy-propyl,
2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methylbutyl,
4-hydroxy-4-methylpentyl, 2-hydroxy-2-ethyl-propyl,
3-hydroxy-3-ethylbutyl and 4-hydroxy-4-ethylpentyl.

[0514]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is R.sup.5 is amino-C.sub.1-6alkyl. In such
embodiments, R.sup.5 may be amino-C.sub.1-6alkyl selected from
amino-methyl, 2-amino-ethyl, 3-amino-propyl, 2-amino-propyl,
2-amino-2-methyl-propyl, 3-amino-3-methylbutyl, 4-amino-4-methylpentyl,
2-amino-2-ethyl-propyl, 3-amino-3-ethylbutyl and 4-amino-4-ethylpentyl.

[0517]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted phenyl. In such embodiments
R.sup.5 may be phenyl optionally substituted once, twice or three times
with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl,
hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or cyano. In certain
embodiments R.sup.5 is phenyl substituted once or twice with halo, cyano,
trifluoromethyl, methanesulfonyl, methoxy, or methyl.

[0518]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted pyridinyl. In such
embodiments R.sup.5 may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl
each optionally substituted once, twice or three times with
C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl,
hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or cyano. In certain
embodiments R.sup.5 is pyridin-2-yl.

[0519]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted pyrazinyl. In certain
embodiments R.sup.5 may be pyrazin-2-yl optionally substituted once,
twice or three times with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano. In certain embodiments R.sup.5 is pyrazin-2-yl

[0520]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted pyrimidinyl. In certain
embodiments R.sup.5 may be pyrimidin-2-yl optionally substituted once,
twice or three times with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano. In certain embodiments R.sup.5 is pyrimidin-2-yl

[0521]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted pyridazinyl. In certain
embodiments R.sup.5 may be pyridazin-3-yl optionally substituted once,
twice or three times with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano. In certain embodiments R.sup.5 is pyridazin-3-yl

[0522]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted thiazolyl. In certain
embodiments R.sup.5 may be thiazolyl-2-yl optionally substituted once or
twice with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl,
hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or cyano.

[0523]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted piperidinyl-C.sub.1-6alkyl.
In such embodiments R.sup.5 may be piperidin-1-ylmethyl,
4-hydroxy-piperidiny-1-ylmethyl, 4-methoxy-piperidin-1-ylmethyl,
4-methanesulfonyl-piperidin-1-ylmethyl, 4-fluoro-piperidin-1-ylmethyl or
4,4-difluoropiperidin-1-ylmethyl.

[0525]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted morpholinyl-C.sub.1-6alkyl.
In such embodiments R.sup.5 may be morpholin-4-ylmethyl.

[0526]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted
thiomorpholinyl-C.sub.1-6alkyl. In such embodiments R.sup.5 may be
thiomorpholin-4-ylmethyl, 1-oxo-thiomorpholin-4-ylmethyl or
1,1,-dioxo-thiomorpholin-4-ylmethyl.

[0527]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is optionally substituted
pyrrolidinyl-C.sub.1-6alkyl. In such embodiments R.sup.5 may be
pyrrolidin-1-ylmethyl or 3-hydroxypyrrolidin-1-ylmethyl.

[0528]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is --C(O)--R.sup.8 wherein R.sup.8 is C.sub.1-6alkyl,
C.sub.1-6alkyloxy, N--C.sub.1-6alkyl-amino, N,N-di-C.sub.1-6alkyl-amino,
heterocyclyl, N--C.sub.3-6cycloalkyl-amino or C.sub.3-6cycloalkyloxy.

[0529]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is --CH.sub.2--C(O)--R.sup.8 wherein R.sup.8 is
C.sub.1-6alkyl, C.sub.1-6alkyloxy, N--C.sub.1-6alkyl-amino,
N,N-di-C.sub.1-6alkyl-amino, heterocyclyl, N--C.sub.3-6cycloalkyl-amino
or C.sub.3-6cycloalkyloxy.

[0530]In certain embodiments of formula I, R.sup.1 is: tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is:

[0534]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is hetero-C.sub.1-6alkyl selected from hydroxymethyl,
2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl.

[0536]In certain embodiments of formula I, R.sup.1 is; tetrazol-1-yl
optionally substituted at the 5-position with C.sub.1-6alkyl,
halo-C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
C.sub.3-6-cycloalkyl; R.sup.2 is phenyl substituted once or twice with
fluoro, chloro or methyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
methyl; and R.sup.5 is heteroaryl selected from pyrazin-2-yl,
pyridazin-3-yl and thiazol-2-yl.

[0537]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl; and

[0560]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is C.sub.1-6alkyl. In such embodiments R.sup.5
may be C.sub.1-6alkyl selected from methyl, ethyl, propyl, isopropyl,
n-butyl, isobutyl, tert-butyl, n-pentyl and isopentyl.

[0561]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is C.sub.1-6alkyloxy-C.sub.1-6alkyl. In such
embodiments R.sup.5 may be C.sub.1-6alkyloxy-C.sub.1-6alkyl selected from
methoxymethyl, ethoxymethyl, 2-(methoxy)-ethyl, 2-(ethoxy)-ethyl,
3-(methoxy)-propyl, 3-(ethoxy)-propyl, 3-methoxy-3-methyl-butyl,
4-methoxy-butyl, and 4-methoxy-4-methyl-pentyl.

[0562]In certain embodiments of formula IIa or IIb, R.sup.11 is fluoro,
chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro, R.sup.13 is
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or cyclopropyl,
and R.sup.5 is C.sub.1-6alkylsulfanyl-C.sub.1-6alkyl. In such embodiments
R.sup.5 may be C.sub.1-6alkylsulfanyl-C.sub.1-6alkyl selected from
methylsulfanylmethyl, ethylsulfanylmethyl, 2-(methylsulfanyl)-ethyl,
2-(ethylsulfanyl)-ethyl, 3-(methylsulfanyl)-propyl, 3-(ethanyl)-propyl,
3-methanesulfanyl-3-methyl-butyl, 4-methanesulfanyl-butyl, and
4-methylsulfanyl-4-methyl-pentyl.

[0563]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is C.sub.1-6alkylsulfonyl-C.sub.1-6alkyl. In
such embodiments R.sup.5 may be C.sub.1-6alkylsulfonyl-C.sub.1-6alkyl
selected from methylsulfonylmethyl, ethylsulfanylmethyl,
2-(methylsulfonyl)-ethyl, 2-(ethylsulfonyl)-ethyl,
3-(methylsulfonyl)-propyl, 3-(ethanyl)-propyl,
3-methanesulfonyl-3-methyl-butyl, 4-methanesulfonyl-butyl, and
4-methylsulfonyl-4-methyl-pentyl.

[0564]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is hydroxy-C.sub.1-6alkyl. In such embodiments
R.sup.5 may be hydroxy-C.sub.1-6alkyl selected from hydroxymethyl,
2-hydroxy-ethyl, 3-hydroxy-propyl, 2-hydroxy-propyl,
2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methylbutyl,
4-hydroxy-4-methylpentyl, 2-hydroxy-2-ethyl-propyl,
3-hydroxy-3-ethylbutyl and 4-hydroxy-4-ethylpentyl.

[0565]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is amino-C.sub.1-6alkyl. In such embodiments,
R.sup.5 may be amino-C.sub.1-6alkyl selected from amino-methyl,
2-amino-ethyl, 3-amino-propyl, 2-amino-propyl, 2-amino-2-methyl-propyl,
3-amino-3-methylbutyl, 4-amino-4-methylpentyl, 2-amino-2-ethyl-propyl,
3-amino-3-ethylbutyl and 4-amino-4-ethylpentyl.

[0568]In certain embodiments of formula IIa or IIb, R.sup.11 is fluoro,
chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro, R.sup.13 is
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or cyclopropyl,
and R.sup.5 is optionally substituted phenyl. In such embodiments R.sup.5
may be phenyl optionally substituted once, twice or three times with
C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl,
hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or cyano. In certain
embodiments R.sup.5 is phenyl substituted once or twice with halo, cyano,
trifluoromethyl, methanesulfonyl, methoxy, or methyl.

[0569]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted pyridinyl. In such
embodiments R.sup.5 may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl
each optionally substituted once, twice or three times with
C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl,
hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or cyano. In certain
embodiments R.sup.5 is pyridin-2-yl.

[0570]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted pyrazinyl. In certain
embodiments R.sup.5 may be pyrazin-2-yl optionally substituted once,
twice or three times with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano. In certain embodiments R.sup.5 is pyrazin-2-yl

[0571]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted pyrimidinyl. In
certain embodiments R.sup.5 may be pyrimidin-2-yl optionally substituted
once, twice or three times with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano. In certain embodiments R.sup.5 is pyrimidin-2-yl.

[0572]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted pyridazinyl. In
certain embodiments R.sup.5 may be pyridazin-3-yl optionally substituted
once, twice or three times with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo,
C.sub.1-6haloalkyl, hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or
cyano. In certain embodiments R.sup.5 is pyridazin-3-yl

[0573]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted thiazolyl. In certain
embodiments R.sup.5 may be thiazolyl-2-yl optionally substituted once or
twice with C.sub.1-6alkyl, C.sub.1-6alkyloxy, halo, C.sub.1-6haloalkyl,
hetero-C.sub.1-6alkyl, C.sub.1-6alkylsulfonyl or cyano.

[0574]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted
piperidinyl-C.sub.1-6alkyl. In such embodiments R.sup.5 may be
piperidin-1-ylmethyl, 4-hydroxy-piperidiny-1-ylmethyl,
4-methoxy-piperidin-1-ylmethyl, 4-methanesulfonyl-piperidin-1-ylmethyl,
4-fluoro-piperidin-1-ylmethyl or 4,4-difluoropiperidin-1-ylmethyl.

[0576]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted
morpholinyl-C.sub.1-6alkyl. In such embodiments R.sup.5 may be
morpholin-4-ylmethyl.

[0577]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen or C.sub.1-6alkyl, and R.sup.5 is optionally
substituted thiomorpholinyl-C.sub.1-6alkyl. In such embodiments R.sup.5
may be thiomorpholin-4-ylmethyl, 1-oxo-thiomorpholin-4-ylmethyl or
1,1,-dioxo-thiomorpholin-4-ylmethyl.

[0578]In certain embodiments of formula IIa, IIb or IIc, R.sup.11 is
fluoro, chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro,
R.sup.13 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or
cyclopropyl, and R.sup.5 is optionally substituted
pyrrolidinyl-C.sub.1-6alkyl. In such embodiments R.sup.5 may be
pyrrolidin-1-ylmethyl or 3-hydroxypyrrolidin-1-ylmethyl.

[0585]In certain embodiments of formula IIa or IIb, R.sup.11 is fluoro,
chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro, R.sup.13 is
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or cyclopropyl,
and R.sup.5 is hetero-C.sub.1-6alkyl selected from hydroxymethyl,
2-hydroxy-2-methyl-pentan-1-yl and methoxymethyl.

[0587]In certain embodiments of formula IIa or IIb, R.sup.11 is fluoro,
chloro or methyl, R.sup.12 is hydrogen, fluoro or chloro, R.sup.13 is
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl or cyclopropyl,
and R.sup.5 is heteroaryl selected from pyrazin-2-yl, pyridazin-3-yl and
thiazol-2-yl.

[0601]Compounds of the present invention can be made by a variety of
methods depicted in the illustrative synthetic reaction schemes shown and
described below.

[0602]The starting materials and reagents used in preparing these
compounds generally are either available from commercial suppliers, such
as Aldrich Chemical Co., or are prepared by methods known to those
skilled in the art following procedures set forth in references such as
Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New
York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier
Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic
Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following
synthetic reaction schemes are merely illustrative of some methods by
which the compounds of the present invention can be synthesized, and
various modifications to these synthetic reaction schemes can be made and
will be suggested to one skilled in the art having referred to the
disclosure contained in this Application.

[0603]The starting materials and the intermediates of the synthetic
reaction schemes can be isolated and purified if desired using
conventional techniques, including but not limited to, filtration,
distillation, crystallization, chromatography, and the like. Such
materials can be characterized using conventional means, including
physical constants and spectral data.

[0604]Unless specified to the contrary, the reactions described herein
preferably are conducted under an inert atmosphere at atmospheric
pressure at a reaction temperature range of from about -78.degree. C. to
about 150.degree. C., more preferably from about 0.degree. C. to about
125.degree. C., and most preferably and conveniently at about room (or
ambient) temperature, e.g., about 20.degree. C.

[0606]In step 1 of Scheme A, nitrobenzoic acid a is subject to iodination
under sulfuric acid conditions to afford iodo-nitrobenzoic acid b.
Benzoic acid compound b is reacted with arylboronic acid compound c in
the presence of tetrakis-(triphenylphosphine)palladium catalyst to afford
biphenyl acid compound d. The acid group of biphenyl acid d is protected
by esterification in step 3 to form biphenyl acid methyl ester e.
Biphenyl ester e is then subject to reduction to form biphenylamine f in
step 4. A cyclization reaction is carried out in step 5 by treating
biphenylamine f with sodium azide and acetal compound g to provide
biphenyl tetrazole compound h. In step 6 the ester group of compound h is
hydrolyzed to give acid compound i. In step 7 an amide formation is
achieved by reaction of biphenyl tetrazole compound i with amine i in the
presence of carbodiimide, to afford compound k, which is a compound of
formula I in accordance with the invention.

[0607]Many variations of Scheme A are possible and will suggest themselves
to those skilled in the art. The aryl boronic acid is shown in step 2 as
being a phenyl boronic acid, but may be replaced by pyridinyl boronic
acids in other embodiments of the invention. In many embodiments amine
compound h is a secondary amine with specific stereochemistry. In certain
embodiments the amide formation of step 7 may be carried out prior to
tetrazole formation in step 5. Methanol in step 3 may be replaced with
other lower alcohols. In certain embodiments arylboronic acid c may be
replaced by the corresponding aryl zinc bromide compound (not shown).

[0609]In step 1 of Scheme B, biphenyl amine compound f undergoes an
N-acylation by reaction with anhydride m to provide amide compound n.
Anhydride m may be replaced with the corresponding acid chloride in many
embodiments. Amide n undergoes cyclization in step 2 by reaction with
sodium azide to yield biphenyl tetrazole compound h. Following the
procedure of Scheme A above, compound h may then be hydrolized in step 3
to form acid compound i, which is reacted amine i to afford compound k,
which is a compound of formula I as noted above.

[0610]As in Scheme A, many variations of Scheme B are possible and will
suggest themselves to those skilled in the art.

[0611]Specific details for producing compounds of the invention are
described in the Examples section below.

[0616]The invention includes pharmaceutical compositions comprising at
least one compound of the present invention, or an individual isomer,
racemic or non-racemic mixture of isomers or a pharmaceutically
acceptable salt or solvate thereof, together with at least one
pharmaceutically acceptable carrier, and optionally other therapeutic
and/or prophylactic ingredients.

[0617]In general, the compounds of the invention will be administered in a
therapeutically effective amount by any of the accepted modes of
administration for agents that serve similar utilities. Suitable dosage
ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most
preferably 1-30 mg daily, depending upon numerous factors such as the
severity of the disease to be treated, the age and relative health of the
subject, the potency of the compound used, the route and form of
administration, the indication towards which the administration is
directed, and the preferences and experience of the medical practitioner
involved. One of ordinary skill in the art of treating such diseases will
be able, without undue experimentation and in reliance upon personal
knowledge and the disclosure of this Application, to ascertain a
therapeutically effective amount of the compounds of the present
invention for a given disease.

[0618]Compounds of the invention may be administered as pharmaceutical
formulations including those suitable for oral (including buccal and
sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral
(including intramuscular, intraarterial, intrathecal, subcutaneous and
intravenous) administration or in a form suitable for administration by
inhalation or insufflation. The preferred manner of administration is
generally oral using a convenient daily dosage regimen which can be
adjusted according to the degree of affliction.

[0619]A compound or compounds of the invention, together with one or more
conventional adjuvants, carriers, or diluents, may be placed into the
form of pharmaceutical compositions and unit dosages. The pharmaceutical
compositions and unit dosage forms may be comprised of conventional
ingredients in conventional proportions, with or without additional
active compounds or principles, and the unit dosage forms may contain any
suitable effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed. The pharmaceutical
compositions may be employed as solids, such as tablets or filled
capsules, semisolids, powders, sustained release formulations, or liquids
such as solutions, suspensions, emulsions, elixirs, or filled capsules
for oral use; or in the form of suppositories for rectal or vaginal
administration; or in the form of sterile injectable solutions for
parenteral use. Formulations containing about one (1) milligram of active
ingredient or, more broadly, about 0.01 to about one hundred (100)
milligrams, per tablet, are accordingly suitable representative unit
dosage forms.

[0620]The compounds of the invention may be formulated in a wide variety
of oral administration dosage forms. The pharmaceutical compositions and
dosage forms may comprise a compound or compounds of the present
invention or pharmaceutically acceptable salts thereof as the active
component. The pharmaceutically acceptable carriers may be either solid
or liquid. Solid form preparations include powders, tablets, pills,
capsules, cachets, suppositories, and dispersible granules. A solid
carrier may be one or more substances which may also act as diluents,
flavouring agents, solubilizers, lubricants, suspending agents, binders,
preservatives, tablet disintegrating agents, or an encapsulating
material. In powders, the carrier generally is a finely divided solid
which is a mixture with the finely divided active component. In tablets,
the active component generally is mixed with the carrier having the
necessary binding capacity in suitable proportions and compacted in the
shape and size desired. The powders and tablets preferably contain from
about one (1) to about seventy (70) percent of the active compound.
Suitable carriers include but are not limited to magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a
low melting wax, cocoa butter, and the like. The term "preparation" is
intended to include the formulation of the active compound with
encapsulating material as carrier, providing a capsule in which the
active component, with or without carriers, is surrounded by a carrier,
which is in association with it. Similarly, cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges may be
as solid forms suitable for oral administration.

[0621]Other forms suitable for oral administration include liquid form
preparations including emulsions, syrups, elixirs, aqueous solutions,
aqueous suspensions, or solid form preparations which are intended to be
converted shortly before use to liquid form preparations. Emulsions may
be prepared in solutions, for example, in aqueous propylene glycol
solutions or may contain emulsifying agents, for example, such as
lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be
prepared by dissolving the active component in water and adding suitable
colorants, flavors, stabilizers, and thickening agents. Aqueous
suspensions can be prepared by dispersing the finely divided active
component in water with viscous material, such as natural or synthetic
gums, resins, methylcellulose, sodium carboxymethylcellulose, and other
well known suspending agents. Solid form preparations include solutions,
suspensions, and emulsions, and may contain, in addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and
natural sweeteners, dispersants, thickeners, solubilizing agents, and the
like.

[0622]The compounds of the invention may be formulated for parenteral
administration (e.g., by injection, for example bolus injection or
continuous infusion) and may be presented in unit dose form in ampoules,
pre-filled syringes, small volume infusion or in multi-dose containers
with an added preservative. The compositions may take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles, for
example solutions in aqueous polyethylene glycol. Examples of oily or
nonaqueous carriers, diluents, solvents or vehicles include propylene
glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and
injectable organic esters (e.g., ethyl oleate), and may contain
formulatory agents such as preserving, wetting, emulsifying or
suspending, stabilizing and/or dispersing agents. Alternatively, the
active ingredient may be in powder form, obtained by aseptic isolation of
sterile solid or by lyophilization from solution for constitution before
use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0623]The compounds of the invention may be formulated for topical
administration to the epidermis as ointments, creams or lotions, or as a
transdermal patch. Ointments and creams may, for example, be formulated
with an aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or oily
base and will in general also containing one or more emulsifying agents,
stabilizing agents, dispersing agents, suspending agents, thickening
agents, or coloring agents. Formulations suitable for topical
administration in the mouth include lozenges comprising active agents in
a flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatine and
glycerine or sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.

[0624]The compounds of the invention may be formulated for administration
as suppositories. A low melting wax, such as a mixture of fatty acid
glycerides or cocoa butter is first melted and the active component is
dispersed homogeneously, for example, by stirring. The molten homogeneous
mixture is then poured into convenient sized molds, allowed to cool, and
to solidify.

[0625]The compounds of the invention may be formulated for vaginal
administration. Pessaries, tampons, creams, gels, pastes, foams or sprays
containing in addition to the active ingredient such carriers as are
known in the art to be appropriate.

[0626]The subject compounds may be formulated for nasal administration.
The solutions or suspensions are applied directly to the nasal cavity by
conventional means, for example, with a dropper, pipette or spray. The
formulations may be provided in a single or multidose form. In the latter
case of a dropper or pipette, this may be achieved by the patient
administering an appropriate, predetermined volume of the solution or
suspension. In the case of a spray, this may be achieved for example by
means of a metering atomizing spray pump.

[0627]The compounds of the invention may be formulated for aerosol
administration, particularly to the respiratory tract and including
intranasal administration. The compound will generally have a small
particle size for example of the order of five (5) microns or less. Such
a particle size may be obtained by means known in the art, for example by
micronization. The active ingredient is provided in a pressurized pack
with a suitable propellant such as a chlorofluorocarbon (CFC), for
example, dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The
aerosol may conveniently also contain a surfactant such as lecithin. The
dose of drug may be controlled by a metered valve. Alternatively the
active ingredients may be provided in a form of a dry powder, for example
a powder mix of the compound in a suitable powder base such as lactose,
starch, starch derivatives such as hydroxypropylmethyl cellulose and
polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the
nasal cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of e.g., gelatine or blister packs
from which the powder may be administered by means of an inhaler.

[0628]When desired, formulations can be prepared with enteric coatings
adapted for sustained or controlled release administration of the active
ingredient. For example, the compounds of the present invention can be
formulated in transdermal or subcutaneous drug delivery devices. These
delivery systems are advantageous when sustained release of the compound
is necessary and when patient compliance with a treatment regimen is
crucial. Compounds in transdermal delivery systems are frequently
attached to an skin-adhesive solid support. The compound of interest can
also be combined with a penetration enhancer, e.g., Azone
(1-dodecylazacycloheptan-2-one). Sustained release delivery systems are
inserted subcutaneously into the subdermal layer by surgery or injection.
The subdermal implants encapsulate the compound in a lipid soluble
membrane, e.g., silicone rubber, or a biodegradable polymer, e.g.,
polylactic acid.

[0629]The pharmaceutical preparations are preferably in unit dosage forms.
In such form, the preparation is subdivided into unit doses containing
appropriate quantities of the active component. The unit dosage form can
be a packaged preparation, the package containing discrete quantities of
preparation, such as packeted tablets, capsules, and powders in vials or
ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or
lozenge itself, or it can be the appropriate number of any of these in
packaged form.

[0630]Other suitable pharmaceutical carriers and their formulations are
described in Remington: The Science and Practice of Pharmacy 1995, edited
by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa.
Representative pharmaceutical formulations containing a compound of the
present invention are described below.

EXAMPLES

[0631]The following preparations and examples are given to enable those
skilled in the art to more clearly understand and to practice the present
invention. They should not be considered as limiting the scope of the
invention, but merely as being illustrative and representative thereof.

[0632]Unless otherwise stated, all temperatures including melting points
(i.e., MP) are in degrees celsius (.degree. C.). It should be appreciated
that the reaction which produces the indicated and/or the desired product
may not necessarily result directly from the combination of two reagents
which were initially added, i.e., there may be one or more intermediates
which are produced in the mixture which ultimately leads to the formation
of the indicated and/or the desired product. The following abbreviations
may be used in the Preparations and Examples.

ABBREVIATIONS

[0633]DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0634]DCM dichloromethane/methylene chloride

[0635]DMF N,N-dimethylformamide

[0636]DMAP 4-dimethylaminopyridine

[0637]EDCI 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide

[0638]EtOAc ethyl acetate

[0639]EtOH ethanol

[0640]gc gas chromatography

[0641]HMPA hexamethylphosphoramide

[0642]HOBt N-Hydroxybenzotriazole

[0643]hplc high performance liquid chromatography

[0644]mCPBA m-chloroperbenzoic acid

[0645]MeCN acetonitrile

[0646]NMM N-methyl-morpholine

[0647]NMP N-methylpyrrolidinone

[0648]TEA triethylamine

[0649]THF tetrahydrofuran

[0650]LDA lithium diisopropylamine

[0651]TLC thin layer chromatography

Preparation 1

4'-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic Acid

[0652]The synthetic procedure used in this preparation is outlined below
in Scheme C.

##STR00060##

Step 1 3-Iodo-5-nitro-benzoic Acid

[0653]To a stirred solution of iodine (137.95 g, 0.5436 mmol) in fuming
sulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g, 0.3866
mmol) at room temperature. The reaction mixture was slowly heated to
85.degree. C. overs 2 hours and stirred at the same temperature for
another 12 hours. The reaction mixture was cooled to room temperature and
poured into ice, and the aqueous solution was extracted with
dichloromethane. The organic phase was separated and washed with water,
2.0 M solution of Na.sub.2S.sub.2O.sub.3 and brine, and then dried over
Na.sub.2SO.sub.4. Solvent was removed under reduced pressure to yield
3-iodo-5-nitrobenzoic acid as slight yellow solid 111 g, yield 98%. MS
(M+H)=294.

Step 2 4'-Methyl-5-nitro-biphenyl-3-carboxylic Acid

[0654]To a stirred solution of 3-iodo-5-nitrobenzoic acid (15.48 g, 52.83
mmol) and Pd(Ph.sub.3P).sub.4 (1.84 g, 1.69 mmol) in 300 ml of toluene
and 50 ml of ethanol was added p-tolylboronic acid (7.87 g, 58.11 mmol)
and a solution of Cs.sub.2CO.sub.3 (18.89 g, 58.11 mmol) in 20 ml water
at room temperature. The reaction was brought to reflux for 18 hours and
then cooled to room temperature. To the solution was added 2N NaOH, and
the reaction mixture was stirred for 30 minutes. The organic phase was
separated, and the aqueous phase was adjusted to PH<4 using 12N HCl.
The resulting solid precipitate was filtered and washed with toluene to
afford 13.2 g of 4'-Methyl-5-nitro-biphenyl-3-carboxylic acid as light
yellow solid (97.2%). MS (M+H)=258.

Step 3 4'-Methyl-5-nitro-biphenyl-3-carboxylic Acid Methyl Ester

[0655]To a solution of 4'-Methyl-5-nitro-biphenyl-3-carboxylic acid (10.00
g, 0.039 mol) in methanol was added SOCl.sub.2 (5.09 g, 0.043 mol) at
0.degree. C. The reaction mixture was allowed to warm to room temperature
and was then heated to reflux for 2 hours. The solvent was removed in
vacuo to afford 4'-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester
(9.72 g, 92%) as light yellow solid. MS (M+H)=273.

Step 4 5-Amino-4'-methyl-biphenyl-3-carboxylic Acid Methyl Ester

[0656]To a solution of 4'-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl
ester (10.00 g, 36.9 mmol) in methanol was added SnCl.sub.2 (27.98 g,
147.6 mmol) at room temperature. The reaction mixture was refluxed for 3
hours, then cooled. Solvent was removed in vacuo and the residue was
dissolved in H.sub.2O, then basified by addition of Na.sub.2CO.sub.3 to
pH=9. The mixture was extracted by CH.sub.2Cl.sub.2, and the organic
phase was washed with water followed by brine, and dried over
Na.sub.2SO.sub.4. The solvent was removed under vacuum to give
5-Amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester (8.48 g, 95%)
as yellow oil. MS (M+H)=242.

[0658]A solution of LiOH.H.sub.2O (1.86 g, 44.2 mmol) in H.sub.2O (40 mL)
was added dropwise to a suspension of
4'-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester (10 g,
34 mmol) in THF (25 mL) at 0.degree. C. The reaction mixture was allowed
to warm to room temperature and was stirred until the reaction solution
turned clear. Solvent was removed under vacuum and the aqueous solution
was acidified by addition of 10% HCl to pH=3. The resulting precipitate
was collected and dried to afford
4'-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid as white solid (8.85
g, 93%). MS (M+H)=281.

[0670]To a solution of 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid
methyl ester (410 mg, 36.9 mmol) in methanol was added SnCl.sub.2 (1.36
g, 6.03 mmol) at room temperature. The reaction mixture was refluxed for
3 hours and then cooled. Solvent was removed in vacuo and the residue was
dissolved in H.sub.2O and basified by Na.sub.2CO.sub.3 to pH=9. The
mixture was extracted with CH.sub.2Cl.sub.2, and the organic phase was
washed with water, brine, and dried over Na.sub.2SO.sub.4. The solvent
was removed under vacuum to give
3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (362 mg,
100%) as yellow oil. MS (M+H)=244.

[0671]To a solution of 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid
methyl ester (362 mg, 1.51 mmol) and NaN.sub.3 (182 g, 2.8 mmol) in AcOH
was added HC(OEt).sub.3 (1074 mg, 7.25 mmol) at room temperature. The
reaction mixture was heated to reflux for 4 hours and then cooled to room
temperature. The solvent was removed in vacuo and the residue was
purified by silica-gel chromatography to give
3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester as a
light yellow solid (440 mg, 100%). MS (M+H)=296.

Step 6 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic Acid

[0672]A solution of LiOH hydrate (82 mg, 1.94 mmol) in H.sub.2O (7 mL) was
added dropwise to a suspension of
3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (440
mg, 1.49 mmol) in THF (4 mL) at 0.degree. C. The reaction mixture was
allowed to warm to room temperature and was stirred until the reaction
solution turned into clear. Solvent was removed under vacuum and the
resulting aqueous solution was acidified by 10% HCl to pH=6-7. The
resulting precipitate was collected and dried to afford
3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid as a yellow solid
(390 mg, 93%). MS (M+H)=282.

[0678]To a solution of 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-nitro-benzoic
acid methyl ester (1000 mg, 3.47 mmol) in methanol was added SnCl.sub.2
(2.63 g, 13.9 mmol) at room temperature. The reaction mixture was
refluxed for 3 hours, then cooled to room temperature. Solvent was
removed in vacuo, and the residue was dissolved in H.sub.2O and basified
by addition of Na.sub.2CO.sub.3 to pH=9. The mixture was extracted with
CH.sub.2Cl.sub.2, and the combined organic phase was washed with water,
brine, and dried over Na.sub.2SO.sub.4. Solvent was removed under vacuum
to give 3-Amino-5-(4-Methyl-2-oxo-2H-pyridin-1-yl)benzoic acid methyl
ester (895 mg, 100%) as yellow solid. MS (M+H)=260.

[0680]A solution of LiOH.H.sub.2O (95 mg, 2.25 mmol) in H.sub.2O (7 mL)
was added dropwise to a suspension of
3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid methyl
ester (500 mg, 1.61 mmol) in THF (4 mL) at 0.degree. C. The reaction
mixture was allowed to warm to room temperature and was stirred until the
reaction solution turned into clear. Solvent was removed under vacuum and
the aqueous solution was acidified by addition of 10% HCl to pH=2. The
resulting precipitate was collected and dried to afford
3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid as yellow
solid (453 mg, 95%). MS (M+H)=298.

Preparation 4

3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide

[0681]The synthetic procedure used in this preparation is outlined below
in Scheme F.

##STR00063##

Step 1 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide

[0682]EDCI (7.07 g, 36.9 mmol) was added in one portion to a stirred
solution of 3-Iodo-5-nitro-benzoic acid (2.31 g, 24.6 mmol), HOBt (4.985
g, 36.9 mmol), 2-Amino-1-methoxypropane (2.73 ml, 24.6 mmol) and NMP
(4.06 ml 36.9 mmol) in CH.sub.2Cl.sub.2 (120 ml) and DMF (10 ml) at
0.degree. C. The reaction was allowed to warm to room temperature and was
stirred over night. The reaction mixture was then washed with 2N NaOH,
water, brine, and dried over Na.sub.2SO.sub.4. Solvent was removed in
vacuo to give 2.50 g of
3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide as a yellow solid,
MS (M+H)=365. This material was used without further purification.

Step 2 3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium

[0683]To a solution of
3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-nitro-benzamide (8.05 g, 20.5 mmol)
in methanol was added SnCl.sub.2 (17.34 g, 76.87 mmol) at room
temperature. The reaction mixture was refluxed for 3 hours. Solvent was
removed in vacuo and the residue was dissolved in H.sub.2O, then basified
by addition of Na.sub.2CO.sub.3 to pH=9. The mixture was extracted with
CH.sub.2Cl.sub.2, and the organic phase was washed with water, brine, and
dried over Na.sub.2SO.sub.4. The solvent was removed under vacuum to give
3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium (7.40 g,
92.5%) as yellow oil. MS (M+H)=336.

Step 3 3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide

[0684]To a solution of
3-Iodo-5-(2-methoxy-1-methyl-ethylcarbamoyl)-phenyl-ammonium (7.47 g,
22.4 mmol) and NaN.sub.3 (2.68 g, 41.2 mmol) in AcOH (100 mL) was added
HC(OEt).sub.3 (18.3 mL, 110 mmol) at room temperature. The reaction
mixture was brought to reflux for 4 hours, then cooled to room
temperature. The solvent was removed in vacuo and the residue was
purified by silica-gel chromatography to give
3-Iodo-N-(2-methoxy-1-methyl-ethyl)-5-tetrazol-1-yl-benzamide as a white
solid (6.30 g, 72%). MS (M+H)=388.

[0688]The synthetic procedure used in this preparation is outlined below
in Scheme G.

##STR00064##

Step 1 (S)-Boc-2-amino-propanol

[0689]D-Alanine (3.5 g, 39.3 mmol) was added in small portions to a
suspension of LiAlH.sub.4 (2.89 g, 76.26 mmol) in refluxing THF.
Refluxing continued for 12 hours, then the reaction mixture was cooled to
0.degree. C., and excess reagent was quenched by careful addition of an
aqueous 15% NaOH solution (3 ml) and water (9 ml). After stirring at room
temperature for 10 minutes, a solution of (Boc).sub.2O (8.31 g, 38.13
mmol) in CH.sub.2Cl.sub.2 (40 ml) was added. The reaction mixture was
stirred at 60.degree. C. for 6 hours, cooled to room temperature,
filtered through a pad of anhydrous Na.sub.2SO.sub.4, and the filtrate
concentrated under vacuum. Purification of the residue by silica-gel
column chromatography afforded (S)-Boc-2-amino-propanol as a white solid,
yield: 63%. MS (M+H)=176.

Step 2 (S)-Boc-2-methoxy-1-methyl-ethylamine

[0690]To a solution of (S)-Boc-2-amino-propanol (2.00 g, 11.4 mmol) was
successively added Ag.sub.2O (5.89 g, 25.4 mmol) and Methyl iodide (16.00
g, 112.7 mmol) at room temperature. The reaction mixture was stirred at
room temperature for 2 days. Solid was filtered off and the filtrate was
concentrated under vacuum to afford (S)-Boc-2-methoxy-1-methyl-ethylamine
as a colorless oil that was used without further purification.

Step 3 (S)-2-methoxy-1-methyl-ethylamine

[0691](S)-Boc-2-methoxy-1-methyl-ethylamine was dissolved in MeOH (40 mL)
and 3 M HCl (10 mL) was added. The reaction mixture was stirred overnight
at room temperature, then solvent was removed under reduced pressure and
the residue was co-evaporated with additional EtOH (20 mL) to afford
(S)-2-methoxy-1-methyl-ethylamine as light-brown oil in hydrochloride
form (1.42 g, 100%). MS (M+H)=90.

[0692]Similarly prepared was (S)-2-ethoxy-1-methyl-ethylamine.

[0693]Similarly prepared from L-alanine were
(R)-2-methoxy-1-methyl-ethylamine and (R)-2-ethoxy-1-methyl-ethylamine.

Preparation 6

(S)-1-Methyl-2-morpholin-4-yl-ethylamine

[0694]The synthetic procedure used in this preparation is outlined below
in Scheme H.

##STR00065##

Step 1 Methanesulfonic acid 2-tert-butoxycarbonylamino-propyl Ester

[0695]To a solution of (S)-Boc-2-amino-propanol (4.91 g, 0.028 mol),
Et.sub.3N (1.5 equiv.) in CH.sub.2Cl.sub.2 at 0.degree. C. was added
methanesulfonyl chloride (1.1-1.2 equiv). The reaction was stirred at
0.degree. C. for 30 minutes. Water (5 ml) was added and the organic layer
was separated, washed with saturated aqueous NaHCO.sub.3, brine, and
dried with MgSO.sub.4. Solvent was removed under vacuum to afford
methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester as a white
solid, yield: 98%. MS (M+H)=254.

[0696]To a solution of methanesulfonic acid
2-tert-butoxycarbonylamino-propyl ester (23 mmol) in CH.sub.3CN (20 mL)
was added morpholine (28 mmol) and K.sub.2CO.sub.3 (23 mmol) at room
temperature. The reaction mixture was brought to 50.degree. C. and kept
at the same temperature overnight. The reaction mixture was cooled and
solvent was removed under reduced pressure, and the residue was treated
with CH.sub.2Cl.sub.2 (50 mL) and H.sub.2O (50 mL). The organic layer was
separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The
combined organic layer was dried over Na.sub.2SO.sub.4. Solvent was
removed under reduced pressure and the residue was purified by column
chromatography (ethyl acetate) to afford
(1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester as
viscous liquid, yield: 62%. MS (M+H)=245.

[0703]A mixture of
2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g,
18.2 mmol) and BH.sub.3 (1 M in THF, 110 mL) was heated to reflux for 48
h, then cooled to room temperature and quenched by MeOH. The volatile was
removed under vacuum. 2 N HCl (100 mL) was added to the residue and
heated to reflux for 18 h. Solvent was removed under vacuum to give
(S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine (4.5
g) as white solid, yield 90%. MS (M+H)=193.

Preparation 8

1-Pyrazin-2-yl-ethyl Amine

[0704]The synthetic procedure used in this preparation is outlined below
in Scheme J.

##STR00067##

[0705]To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmol) and
ammonium acetate (19.337 g, 158.5 mmol) in methanol (50 mL) was added
sodium cyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction
mixture was stirred overnight at room temperature. After removal of
methanol, water (20 mL) was added to the residue and the resulting
solution was basified by addition of sodium hydroxide to pH=13. The
aqueous solution was extracted with dichloromethane and the combined
organic phase was dried over sodium sulfate. Removal of the solvent under
reduced pressure afforded 14.62 g of 1-pyrazin-2-yl-ethylamine, yield:
75%. MS (M+H)=124.

[0708]3-Bromo-5-iodo-benzoic acid methyl ester (14.16 g, 41.53 mmol),
bis(pinacolato)-diborane (11.60 g, 45.7 mmol), PdCl.sub.2(dppf).sub.2
(1.02 g, 1.256 mmol) and potassium acetate (12.22 g, 124.6 mmol) were
added to 50 mL of DMSO, and the reaction mixture was stirred at
80.degree. C. for 20 hours, then cooled to room temperature. The reaction
mixture was diluted with water and extracted with diethyl ether. The
combined organic extracts were dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure to give 18.5 g of
3-bromo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid
methyl ester, which was used directly in the next step without further
purification.

[0716]2-Fluoro-5-iodo-3-nitro-benzoic acid (2.0 g, 6.43 mmol) and
SOCl.sub.2 (918 mg, 7.72 mmol) were added to 20 mL MeOH, and the mixture
was refluxed for two hours and then cooled to room temperature. Solvent
was evaporated under reduced pressure and the residue was dissolved in
EtOAa. The EtOAc solution was washed with brine, dried over NaSO.sub.4,
filtered and concentrated under reduced pressure to give 2.0 g (96%) of
2-fluoro-5-iodo-3-nitro-benzoic acid methyl ester.

Step 3 3-Amino-2-fluoro-5-iodo-benzoic Acid Methyl Ester

[0717]2-Fluoro-5-iodo-3-nitro-benzoic acid methyl ester (1.0 g, 3.08 mmol)
and SnCl.sub.2 (2.33 g, 12.3 mmol) were added to 20 mL EtOAc, and the
mixture was heated to reflux for two hours. The reaction mixture was
cooled to room temperature and concentrated under reduced pressure. The
residue was dissolved in 20 mL saturated aqueous NaHCO.sub.3, and the
aqueous mixture was extracted with EtOAc. The combined organic layers
were washed with and brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure to give 560 mg (62%) of
3-amino-2-fluoro-5-iodo-benzoic acid methyl ester, MS (M+H)=296.

[0728]A solution of LiOH--H.sub.2O (39.1 mg, 0.931 mmol) in H.sub.2O (8
mL) was added dropwise to a suspension of
5-(1-ethyl-1H-tetrazol-5-yl)-4'-methyl-biphenyl-3-carboxylic acid methyl
ester (200 mg, 0.621 mmol) in THF (5 mL) at 0.degree. C. The reaction
mixture was allowed to warm to room temperature and was stirred until the
mixture turned clear. THF was removed under vacuum and the aqueous
solution was acidified by 10% HCl to pH=3. The precipitate was collected
and dried to afford
5-(1-ethyl-1H-tetrazol-5-yl)-4'-methyl-biphenyl-3-carboxylic acid as
white solid (162 mg, 84%). MS (M+H)=309.

[0734]To a stirred solution of
4'-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid
methyl ester (3.7 mmol, 1.34 g) in 50 ml of THF was added a solution of
LiOH.H.sub.2O (18.5 mmol, 776.3 mg) in 12 mL of water. The reaction
mixture was heated to reflux for 3.5 hours, then cooled to room
temperature. Solvent was removed under reduced pressure, and the pH of
the liquid residue was adjusted to 2.0 by addition of 2N aqueous HCl
solution. The mixture was extracted with ethyl acetate and the combined
ethyl acetate layers were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo to give
4'-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid
as light yellow solid (1.25 g, 97% yield).

[0741]To a stirred solution of
4'-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl
ester (1 mmol, 308 mg) in 10 ml of THF was added a solution of
LiOH.H.sub.2O (5 mmol, 210 mg) in 2 mL of water. The reaction mixture was
heated to reflux for 3.5 hours and then cooled to room temperature.
Solvent was removed under reduced pressure and the liquid residue was pH
adjusted to 2.0 by addition of 2N aqueous HCl solution. The mixture was
extracted with ethyl acetate and the combined ethyl acetate layers were
dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give
4'-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid as white
solid (279 mg, 95% yield).

[0746]3-(2,2-Difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic
acid methyl ester (0.630 g, 1.88 mmol) and triphenyl phosphine (0.989 g,
3.77 mmol) were added to 15 mL of CCl.sub.4. The reaction mixture was
heated to 95.degree. C. and stirred under nitrogen for 48 hours. The
reaction mixture was filtered, and the filtrate was concentrated under
reduced pressure to give 0.612 g of
3-(1-chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benz-
oic acid methyl ester, which was used directly in the next step without
further purification.

[0748]3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-b-
enzoic acid methyl ester (0.605 g, 0.68 mmol) was added to a mixture of
methanol (10 mL), methylene chloride (2 mL) and 3N aqueous NaOH (0.5 mL).
The reaction mixture was stirred at room temperature for 18 hours, then
solvent was removed under reduced pressure. The liquid residue was
diluted with water and acidified to pH 5 by addition of 1N aqueous HCl.
The resulting mixture was extracted with EtOAc, and the combined organic
layers were washed with water, dried (MgSO.sub.4), filtered and
concentrated under reduced pressure to give 0.552 g of
3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoi-
c acid.

[0772]2-Fluoro-5-(5-isopropyl-tetrazol-1-yl)-3-(5-methyl-pyridin-2-yl)-ben-
zoic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine using the
procedure of step 4 of Example 7 to provide
2-fluoro-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-3--
(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=447.

[0773]Additional compounds prepared by the above procedure are shown in
Table 1.

Example 9

Formulations

[0774]Pharmaceutical preparations for delivery by various routes are
formulated as shown in the following Tables. "Active ingredient" or
"Active compound" as used in the Tables means one or more of the
Compounds of Formula I.

[0778]The ingredients are combined and granulated using a solvent such as
methanol. The formulation is then dried and formed into tablets
(containing about 20 mg of active compound) with an appropriate tablet
machine.

[0782]The active ingredient is dissolved in a portion of the water for
injection. A sufficient quantity of sodium chloride is then added with
stirring to make the solution isotonic. The solution is made up to weight
with the remainder of the water for injection, filtered through a 0.2
micron membrane filter and packaged under sterile conditions.

[0786]All of the ingredients, except water, are combined and heated to
about 60.degree. C. with stirring. A sufficient quantity of water at
about 60.degree. C. is then added with vigorous stirring to emulsify the
ingredients, and water then added q.s. about 100 g.

[0788]CHO-K1 cells were transfected with cloned rat P2X.sub.3 or human
P2X.sub.2/3 receptor subunits and passaged in flasks. 18-24 hours before
the FLIPR experiment, cells were released from their flasks, centrifuged,
and resuspended in nutrient medium at 2.5.times.10.sup.5 cells/ml. The
cells were aliquoted into black-walled 96-well plates at a density of
50,000 cells/well and incubated overnight in 5% CO.sub.2 at 37.degree. C.
On the day of the experiment, cells were washed in FLIPR buffer (calcium-
and magnesium-free Hank's balanced salt solution, 10 mM HEPES, 2 mM
CaCl.sub.2, 2.5 mM probenecid; FB). Each well received 100 .mu.l FB and
100 .mu.l of the fluorescent dye Fluo-3 AM [2 .mu.M final conc.]. After a
1 hour dye loading incubation at 37.degree. C., the cells were washed 4
times with FB, and a final 75 .mu.l/well FB was left in each well.

[0789]Test compounds (dissolved in DMSO at 10 mM and serially diluted with
FB) or vehicle were added to each well (25 .mu.l of a 4.times. solution)
and allowed to equilibrate for 20 minutes at room temperature. The plates
were then placed in the FLIPR and a baseline fluorescence measurement
(excitation at 488 nm and emission at 510-570 nm) was obtained for 10
seconds before a 100 .mu.l/well agonist or vehicle addition. The agonist
was a 2.times. solution of .alpha.,.beta.-meATP producing a final
concentration of 1 .mu.M (P2X.sub.3) or 5 .mu.M (P2X.sub.2/3).
Fluorescence was measured for an additional 2 minutes at 1 second
intervals after agonist addition. A final addition of ionomycin (5 .mu.M,
final concentration) was made to each well of the FLIPR test plate to
establish cell viability and maximum fluorescence of dye-bound cytosolic
calcium. Peak fluorescence in response to the addition of
.alpha.,.beta.-meATP (in the absence and presence of test compounds) was
measured and inhibition curves generated using nonlinear regression.
PPADS, a standard P2X antagonist, was used as a positive control.

[0790]Using the above assay, the compounds of Table 1 were all determined
to be active for the P2X3 receptor. Most of the compounds have an IC50
between about 6.0 and about 8.8 for P2X3. Many of the compounds have an
IC50 of between about 8.0 and about 8.8 for P2.times.3. For example,
5-(5-isobutyl-tetrazol-1-yl)-4'-methyl-biphenyl-3-carboxylic acid
((S)-2-hydroxy-1-methyl-ethyl)-amide exhibited an IC50 of about 8.8.

[0791]Using the above assay, most of the compounds of Table 1 were
determined to be active for the P2X2/3 receptor. Most of the compounds
have an IC50 between about 5.5 and about 8.1 for P2X2/3. Many of the
compounds have an IC50 of between about 7.0 and about 8.1 for P2X2/3. For
example, 5-(5-ethyl-tetrazol-1-yl)-4'-methyl-biphenyl-3-carboxylic acid
(1-pyrazin-2-yl-ethyl)-amide exhibited and IC50 of about 8.1.

Example 10

In Vivo Assay for Asthma and Lung Function

[0792]BALb/cJ mice are immunized with a standard immunization protocol.
Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 fig)
in alum on days 0 and 14. Mice are then challenged with aerosolized OVA
(5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound of
the invention (100 mg/kg p.o.) all starting on day 20.

[0793]Lung function is evaluated on day 23 using the Buxco system to
measure PenH in response to an aerosol methacholine challenge. Mice are
then euthanized and plasma samples collected at the end of the study.

Example 11

Volume Induced Bladder Contraction Assay

[0794]Female Sprague-Dawley rats (200-300 g) were anesthetized with
urethane (1.5 g/kg, sc). The animals were tracheotomized, and a carotid
artery and femoral vein were cannulated for blood pressure measurement
and drug administration, respectively. A laparotomy was performed and the
ureters were ligated and transected proximal to the ligation. The
external urethral meatus was ligated with silk suture and the urinary
bladder was cannulated via the dome for saline infusion and bladder
pressure measurement.

[0795]Following a 15-30 minute stabilization period the bladder was
infused with room temperature saline at 100 .mu.l/min until continuous
volume-induced bladder contractions (VIBCs) were observed. The infusion
rate was then lowered to 3-5 .mu.l/min for 30 minutes before the bladder
was drained and allowed to rest for 30 minutes. All subsequent infusions
were performed as indicated except the lower infusion rate was maintained
for only 15 minutes instead of 30 minutes. Bladder filling and draining
cycles were repeated until the threshold volumes (TV; the volume needed
to trigger the first micturition bladder contraction) varied by less than
10% for two consecutive baselines and contraction frequency was within 2
contractions for a 10 minute period following the slower infusion rate.
Once reproducible TVs and VIBCs were established the bladder was drained
and the animal was dosed with drug or vehicle (0.5 ml/kg, i.v.) 3 minutes
prior to the start of the next scheduled infusion.

Example 12

Formalin Pain Assay

[0796]Male Sprague Dawley rats (180-220 g) are placed in individual
Plexiglas cylinders and allowed to acclimate to the testing environment
for 30 min. Vehicle, drug or positive control (morphine 2 mg/kg) is
administered subcutaneously at 5 ml/kg. 15 min post dosing, formalin (5%
in 50 .mu.l) is injected into plantar surface of the right hind paw using
a 26-gauge needle. Rats are immediately put back to the observation
chamber. Mirrors placed around the chamber allow unhindered observation
of the formalin-injected paw. The duration of nociphensive behavior of
each animal is recorded by a blinded observer using an automated
behavioral timer. Hindpaw licking and shaking/lifting are recorded
separately in 5 min bin, for a total of 60 min. The sum of time spent
licking or shaking in seconds from time 0 to 5 min is considered the
early phase, whereas the late phase is taken as the sum of seconds spent
licking or shaking from 15 to 40 min. A plasma sample is collected.

Example 13

Colon Pain Assay

[0797]Adult male Sprague-Dawley rats (350-425 g; Harlan, Indianapolis,
Ind.) are housed 1-2 per cage in an animal care facility. Rats are deeply
anesthetized with pentobarbital sodium (45 mg/kg) administered
intraperitoneally. Electrodes are placed and secured into the external
oblique musculature for electromyographic (EMG) recording. Electrode
leads are tunneled subcutaneously and exteriorized at the nape of the
neck for future access. After surgery, rats are housed separately and
allowed to recuperate for 4-5 days prior to testing.

[0798]The descending colon and rectum are distended by pressure-controlled
inflation of a 7-8 cm-long flexible latex balloon tied around a flexible
tube. The balloon is lubricated, inserted into the colon via the anus,
and anchored by taping the balloon catheter to the base of the tail.
Colorectal distension (CRD) is achieved by opening a solenoid gate to a
constant pressure air reservoir. Intracolonic pressure is controlled and
continuously monitored by a pressure control device. Response is
quantified as the visceromotor response (VMR), a contraction of the
abdominal and hindlimb musculature. EMG activity produced by contraction
of the external oblique musculature is quantified using Spike2 software
(Cambridge Electronic Design). Each distension trial lasts 60 sec, and
EMG activity is quantified for 20 sec before distension (baseline),
during 20 sec distension, and 20 sec after distention. The increase in
total number of recorded counts during distension above baseline is
defined as the response. Stable baseline responses to CRD (10, 20, 40 and
80 mmHg, 20 seconds, 4 minutes apart) are obtained in conscious,
unsedated rats before any treatment.

[0799]Compounds are evaluated for effects on responses to colon distension
initially in a model of acute visceral nociception and a model of colon
hypersensitivity produced by intracolonic treatment with zymosan (1 mL,
25 mg/mL) instilled into the colon with a gavage needle inserted to a
depth of about 6 cm. Experimental groups will consist of 8 rats each.

[0800]Acute visceral nociception: For testing effects of drug on acute
visceral nociception, 1 of 3 doses of drug, vehicle or positive control
(morphine, 2.5 mg/kg) are administered after baseline responses are
established; responses to distension are followed over the next 60-90
minutes.

[0801]Visceral hypersensitivity: For testing effects of drug or vehicle
after intracolonic treatment with zymosan, intracolonic treatment is
given after baseline responses are established. Prior to drug testing at
4 hours, responses to distension are assessed to establish the presence
of hypersensitivity. In zymosan-treated rats, administration of 1 of 3
doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) are
given 4 hours after zymosan treatment and responses to distension
followed over the next 60-90 minutes.

Example 14

Cold Allodynia in Rats with a Chronic Constriction Injury of the Sciatic
Nerve

[0802]The effects of compounds of this invention on cold allodynia are
determined using the chronic constriction injury (CCI) model of
neuropathic pain in rats, where cold allodynia is measured in a
cold-water bath with a metal-plate floor and water at a depth of 1.5-2.0
cm and a temperature of 3-4.degree. C. (Gogas, K. R. et al., Analgesia,
1997, 3, 1-8).

[0803]Specifically, CCI, rats are anesthetized; the trifurcation of the
sciatic nerve is located and 4 ligatures (4-0, or 5-0 chromic gut) are
placed circumferentially around the sciatic nerve proximal to the
trifurcation. The rats are then allowed to recover from the surgery. On
days 4-7 after surgery, the rats are initially assessed for cold-induced
allodynia by individually placing the animals in the cold-water bath and
recording the total lifts of the injured paw during a 1-min period of
time: The injured paw is lifted out of the water. Paw lifts associated
with locomotion or body repositioning are not recorded. Rats that
displayed 5 lifts per min or more on day 4-7 following surgery are
considered to exhibit cold allodynia and are used in subsequent studies.
In the acute studies, vehicle, reference compound or compounds of this
invention are administered subcutaneously (s.c.) 30 min before testing.
The effects of repeated administration of the compounds of this invention
on cold allodynia are determined 14, 20 or 38 h following the last oral
dose of the following regimen: oral (p.o.) administration of vehicle,
reference or a compound of this invention at .about.12 h intervals (BID)
for 7 days.

Example 15

Cancer Bone Pain in C3H/HeJ Mice

[0804]The effects of compounds of this invention on bone pain are
determined between Day 7 to Day 18 following intramedullary injection of
2472 sarcoma cells into the distal femur of C3H/HeJ mice.

[0805]Specifically, NCTC 2472 tumor cells (American Type Culture
Collection, ATCC), previously shown to form lytic lesions in bone after
intramedullary injection, are grown and maintained according to ATCC
recommendations. Approximately 10.sup.5 cells are injected directly into
the medullary cavity of the distal femur in anesthetized C3H/HeJ mice.
Beginning on about Day 7, the mice are assessed for spontaneous
nocifensive behaviors (flinching & guarding), palpation-evoked
nocifensive behaviors (flinching & guarding), forced ambulatory guarding
and limb use. The effects of compounds of this invention are determined
following a single acute (s.c.) administration on Day 7-Day 15. In
addition, the effects of repeated (BID) administration of compounds of
this invention from Day 7-Day 15 are determined within 1 hour of the
first dose on Days 7, 9, 11, 13 and 15.

[0806]While the present invention has been described with reference to the
specific embodiments thereof, it should be understood by those skilled in
the art that various changes may be made and equivalents may be
substituted without departing from the true spirit and scope of the
invention. In addition, many modifications may be made to adapt a
particular situation, material, composition of matter, process, process
step or steps, to the objective spirit and scope of the present
invention. All such modifications are intended to be within the scope of
the claims appended hereto.